Carbamates of 2-heterocyclic-1,2-ethanediols

ABSTRACT

Carbamate compounds of 2-heteroaryl-1,2-ethanediol are described. The compounds are effective in the treatment of disorders of the central nervous system, especially as anti-convulsive or anti-epileptic agents.

[0001] This Application claims priority from U.S. ProvisionalApplication 60/300,730 filed Jun. 25, 2001.

FIELD OF THE INVENTION

[0002] The invention relates to pharmaceutically useful compounds forthe treatment of central nervous system disorders; particularly usefulas anticonvulsants, antiepileptics, neuroprotective agents and musclerelaxants. More specifically, the invention relates to carbamates of2-heterocyclic-1,2-ethanediols

BACKGROUND

[0003] Chiral or racemic carbamate compounds of aryl alkanols have beenknown to be useful as antiepileptics and as muscle relaxants. In U.S.Pat. No. 5,854,283, the optically pure forms of monocarbamate ofhalogenated 2-phenyl-1,2-ethanediol and dicarbamate of2-phenyl-1,2-ethanediol have been found to be effective in the treatmentof disorders of the central nervous system, especially asanti-convulsive or anti-epileptic agents.

[0004] It has been reported in Toxicol. and Appl. Pharm. 2, 397-402(1960) that (2-phenyl-2-hydroxyethyl)oxocarboxamide is effective as anantiepileptic agent. Dicarbamates of 2-methyl-3-propyl-1,3-propanedioland their pharmacological effects have been described in J. Pharmacol.Exp. Ther., 104, 229 (1952).

[0005] In U.S. Pat. No. 2,884,444, dicarbamates of2-phenyl-1,3-propanediol have been disclosed. Also, in U.S. Pat. No.2,937,119 carbamates, such as isopropylmeprobamate have been disclosed.

[0006] Some of the carbamates described in the previous paragraphs arecurrently being used in the treatment of central nervous systemdisorders.

[0007] In accordance with the present invention there are providedcarbamates of 2-heterocyclic-1,2-ethanediols, including pharmaceuticalcompositions containing them as the active ingredient and methods ofusing the pharmaceutical compositions in the treatment of diseases ofthe central nervous system.

SUMMARY OF THE INVENTION

[0008] The invention relates to compounds of the formula

[0009] wherein A is a heterocyclic moiety optionally substituted by oneor more substituents selected from the group consisting of alkyl, aryl,halogen, trihalomethyl, trihalomethoxy, trialkylsilyl, S(O)R, SO₂R,SO₂NRR′, SO₃R, SR, NO₂, NRR′, OR, CN, C(O)R, OC(O)R, NHC(O)R, CO₂R andCONRR′, wherein R and R′ are independently hydrogen, alkyl or aryl; B₁and B₂ are independently hydroxy or OCONR₁R₂, provided that B₁ and B₂are not simultaneously hydroxy, and R₁ and R₂ are independently selectedfrom the group consisting of hydrogen, hydroxy, alkyl, alkoxy,alkylaryl, arylalkyl, aryl and aryloxy, and their enantiomers, as wellas enantiomeric mixtures, and pharmaceutically acceptable salts thereof.

[0010] The compounds of formula I, their enantiomers, as well asenantiomeric mixtures, and pharmaceutically acceptable salts thereof areuseful in the treatment of central nervous system diseases,particularly, as anticonvulsants, antiepileptics, neuroprotective agentsand centrally acting muscle relaxants.

DETAILED DESCRIPTION OF THE INVENTION

[0011] The invention relates to compounds of the formula

[0012] wherein A is a heterocyclic moiety optionally substituted by oneor more substituents selected from the group consisting of alkyl, aryl,halogen, trihalomethyl, trihalomethoxy, trialkylsilyl, S(O)R, SO₂R,SO₂NRR′, SO₃R, SR, NO₂, NRR′, OR, CN, C(O)R, OC(O)R, NHC(O)R, CO₂R andCONRR′, wherein R and R′ are independently hydrogen, alkyl or aryl; B₁and B₂ are independently hydroxy or OCONR₁R₂, provided that B₁ and B₂are not simultaneously hydroxy,: and R₁ and R₂ are independentlyselected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy,alkylaryl, arylalkyl, aryl and aryloxy, and their enantiomers, as wellas enantiomeric mixtures, and pharmaceutically acceptable salts thereof.

[0013] A preferred group of compounds of the present invention arecompounds of formula (I) wherein A is selected from the group consistingof

[0014] wherein R₃, R₄ and R₅, each independently, is selected from thegroup consisting of hydrogen, alkyl and aryl, and X is selected fromsulfur, oxygen and nitrogen.

[0015] A more preferred compounds of according to the present inventionare compounds of formula I wherein A is

[0016] wherein R₃, R₄ and R₅ are as previously described.

[0017] Illustrative of the compounds of formula (I) are the following:

[0018] (±)-(2-(5-chloro-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide.

[0019](+)-(2R)-(2-(5-chloro-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide;

[0020](−)-(2S)-(2-(5-chloro-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide;

[0021](2-(5-trifluoromethyl-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide.

[0022] (2-(5-bromo-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide.

[0023] (2-(2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide;

[0024]N-methyl-(2-(5-chloro-2-thienyl)-2-N-methylcarbamoyloxyethyl)oxocarboxamide;

[0025] (2-(5-phenyl-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide;

[0026](2-(3,4,5-trichloro-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide;

[0027] (2-(5-methyl-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide;

[0028] (2-(2,5-dichloro-3-thienyl)-2-carbamoyloxyethyl)oxocarboxamide;

[0029] (2-(2-benzothienyl)-2-carbamoyloxyethyl)oxocarboxamide; and

[0030] (2-(5-tert-butyl-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide.

[0031] As used herein, the term “lower alkyl” is to be understood tomean a straight-or branched-chain alkyl group of 1 to 6 carbon atoms,such as methyl, ethyl, isopropyl, butyl, pentyl, hexyl, and the likewith methyl being preferred. The term “halogen” is to be understood tomean all of the halogens, that is, bromine, chlorine, fluorine andiodine; with bromine and chlorine being preferred. The term “loweralkoxy” is to be understood to mean a lower alkyl ether group in whichthe lower alkyl moiety is as described above, such as methoxy, ethoxy,propoxy, butoxy and the like with methoxy being preferred.

[0032] Additional examples of the heterocyclic groups represented by Ain formula (I) include the following:

[0033] and the like, wherein each R₁₀ is the same or different andrepresents a substituent selected from the group consisting of hydrogen,alkyl, aryl, halogen, trihalomethyl, trihalomethoxy, trialkylsilyl,S(O)R, SO₂R, SO₂NRR′, SO₃R, SR, NO₂, NRR′, OR, CN, C(O)R, OC(O)R,NHC(O)R, CO₂R and CONRR′, m is 1-3; and R and R′ are independentlyselected from the group consisting of hydrogen, alkyl and aryl.

[0034] The starting materials for the compounds of the present inventionare represented by the general formula

[0035] wherein A is a heterocyclic ring as defined above. These2-heterocyclic-1,2-ethanediols are known per se or can be convenientlyprepared by a dihydroxylation reaction of the corresponding styreniccompound. Optically active diols can be prepared according to theprocedure given in K. Sharpless et. al., J. Org. Chem 56: 4585˜8(1991).

[0036] The compounds of formula I above wherein only one of B₁ and B₂ isa carbamate group can be prepared by the synthetic method described inScheme 1, a detailed description of which follows. The2-heterocyclic-1,2-ethanediol starting material is reacted with dimethylcarbonate in the presence of catalytic amount of sodium methoxide. Theby-product that forms is removed by vacuum distillation and the residualproduct dried in vacuo. The crude reaction product is subsequentlydissolved in a lower alkanol, such as methanol, and an excess amount ofan amine is added to the reaction solution at room temperature toprovide two regioisomeric forms of a monocarbamate of2-heterocyclic-1-2-ethanediol.

[0037] The compounds of the present invention wherein both of B₁ and B₂are carbamate groups and the carbamate groups are the same may beprepared directly from the 2-heterocyclic-1-2-ethanediol startingmaterial according to the reaction of Reaction Scheme 2 as describedbelow. The 2-heterocyclic-1-2-ethanediol is dissolved in dichloromethaneand is treated with about 2 equivalents of carbonyl diimidazole. Theresulting mixture is stirred until the starting material is not observedby thin layer chromatography analysis, and the mixture is then treatedwith excess amounts of amine (R₁R₂NH wherein R₁ and R₂ are as definedabove). It takes more than 24 hours to complete the reaction. After aroutine aqueous wash, the crude reaction product is purified by flashcolumn chromatography or recrystallization to provide the desiredcompound of formula I.

[0038] The compounds of the present invention wherein both of B₁ and B₂are carbamate groups and the carbamate groups are different may beprepared from the corresponding monocarbamate compound represented byformula I in accordance with Reaction Scheme 3. The2-heterocyclic-1-2-ethanediol monocarbamate is treated with about 1equivalent of carbonyl diimidazole. The resulting mixture is stirreduntil the starting material is not observed by thin layer chromatographyanalysis, after which the mixture is treated with an excess amount ofamine (R₁R₂NH wherein R₁ and R₂ are as defined above, but are differentin at least one particular from those of the starting material).

[0039] Exemplary of the 2-heterocyclic-1,2-ethanediols startingmaterials in accordance with the present invention are the following:

[0040] 1-(2-thienyl)-1,2-ethanediol;

[0041] 1-(5-chloro-2-thienyl)-1,2-ethanediol;

[0042] 1-(5-phenyl-2-thienyl)-1,2-ethanediol;

[0043] 1-(3,4,5-trichloro-2-thienyl)-1,2-ethanediol;

[0044] 1-(2-benzothienyl)-1,2-ethanediol;

[0045] 1-(5-cyano-2-thienyl)-1,2-ethanediol;

[0046] 1-(2-furanyl)-1,2-ethanediol; and the like.

[0047] The compounds of the invention contain chiral centers. Thecompounds of formula (I) contain an asymmetric carbon atom at theposition, which is the aliphatic carbon adjacent to the heteroaromaticring. The scope of the invention includes pure enantiomeric forms andenantiomeric mixtures, wherein one of the enantiomer predominates in thecompound of formula (I). Preferably, one of the enantiomers predominatesto the extent of about 90% or greater, and most preferably, about 98% orgreater.

[0048] The compounds of formula (I) of the invention, which have basicamine functional group like as amino, pyridyl or imidazolyl can formsalts with inorganic and organic acids including, for example,hydrochloric acid, hydrobromic acid, methanesulfonic acid, and the like.These salts are prepared following procedures well known to thoseskilled in the art.

[0049] In utilizing the compounds of the invention for the treatment ofdiseases of the central nervous system, particularly the treatment ofconvulsions, epilepsy, neurogenic pain, stroke and muscle spasm, it ispreferred to administer the compounds orally. Moreover, since thecompounds of formula (I) are absorbed orally, it will not be necessaryto resort to parenteral administration. For oral administration, thecompounds of formula (I) are preferably combined with a pharmaceuticalcarrier. The ratio of the carrier to a compound of formula (I) is notcritical to achieve the desired effects on the central nervous system ofthe host requiring such treatment, and can vary considerably, dependingon whether the composition is to be filled into capsules or formed intotablets. In tableting, it is usually desirable to employ at least asmuch pharmaceutical carrier as the pharmaceutically active ingredients.Various pharmaceutical carriers or mixtures thereof can be used.Suitable carriers, for example, comprise mixtures of lactose, dibasiccalcium phosphate and corn starch. Other pharmaceutically acceptableingredients can be further added, including lubricants such as magnesiumstearate.

[0050] The compounds of formula (I) can be formulated, usingconventional inert pharmaceutical adjuvant materials, into dosage formsthat are suitable for oral or parenteral administration. Such dosageforms include tablets, suspensions, solutions, and the like.Furthermore, the compounds of the invention can be administered in theform of hard or soft capsules. Examples of suitable inert adjuvantmaterials that can be used in formulating the compounds of formula (I)into oral and parenteral dosage forms will be immediately apparent topersons skilled in the art. These adjuvant materials include, forexample, water, gelatin, lactose, starch, magnesium stearate, talc,vegetable oils, gums, polyalkylene glycols, and the like. Moreover,preservatives, stabilizers, wetting agents, emulsifying agents, saltsfor altering osmotic pressure, buffers, and the like, can beincorporated, if desired, into such formulations.

[0051] The therapeutic use of the compounds of formula I asanticonvulsants has been established by the “Maximal ElectroShock (MES)”test, which is a well-established pharmacological screening method foranticonvulsants against partial seizures, and the results are presentedin Table I. The procedure employed in the MES test for anticonvulsantsis as follows. The dosing solutions of the compounds to be tested wereprepared in saline. The subjects, namely, mice (ICR strain), were dosedi.p. After the designated number of hours, maximal electroshock wasinduced in mice via corneal electrodes using IITC Life Science model 11AShocker at 50 mA-60 Hz for 0.2 second. Anticonvulsant activity isdemonstrated by the elimination of hindlimb tonic extension uponinducing maximal electroshock. Median efficacy dose (ED₅₀) levels weredetermined using three different dose levels with at least 6 mice ineach group. Compounds with smaller ED₅₀ value are more potent asanticonvulsants.

[0052] The “Pentylenetetrazol (PTZ)” test for anticonvulsant activitywas also carried out. Compounds that antagonize the effects ofsubcutaneous PTZ-induced seizures are known to elevate the threshold forseizures, hence are generally useful in preventing such seizures. Theprocedure employed in the PTZ test for anticonvulsants follows. Thecompound dosing solutions were prepared in saline, and mice (ICRstrain), were dosed i.p. After the designated number of hours, eachanimal was injected subcutaneously with 100 mg/kg of PTZ(CD₉₇ dose) andobserved for up to 30 minutes for the presence or absence of thresholdclonic seizures of 2 second duration or longer. Median efficacy dose(ED₅₀) levels were determined using three different dose levels with 8mice in each group. The compounds with a smaller ED₅₀ value are morepotent as anticonvulsants.

[0053] Test results obtained with the compounds of formula I of theinvention are set forth in Table I. TABLE 1 Compound MES PTZ Of ED₅₀ED₅₀ Example (mg/Kg) (mg/Kg) Hour 4 16.9 31.3 2 5 8.4 47.2 2 6 36.9 42.72 7 37.4 — 1 14  12.6 — 1 17  14.9 50 1 18  19.6 — 1

[0054] The data presented in Table 1 demonstrate that the compounds offormula (I) of the invention possess anticonvulsant activity bypreventing the occurrence of electroshock seizures, and also protectingthe host against convulsions produced by pentylenetetrazole.

[0055] The amount of a compound of formula (I) which is present in anyof the above-described dosage forms is variable. In the systemictreatment of CNS diseases with a active amount of compounds of theformula (I), the dosage is typically from about 0.02 mg to about 250mg/kg/day (0.001˜12.5 g/day in a typical human weighing 50 kg) in singleor divided doses, regardless of the route of administration. A morepreferred dosage range is from about 0.15 mg/kg/day to about 250mg/kg/day. Of course, depending upon the exact compound and the exactnature of the individual illness, doses outside this range may beprescribed by the attending physician.

[0056] The examples, which follow further, illustrate the invention. Allparts are by weight and all temperatures are in degrees centigrade,unless otherwise mentioned.

[0057] Moreover, unless otherwise stated, NMR spectra were obtained at200 Mhz, melting points are uncorrected, and optical rotations weremeasured with a automatic polarimeter.

EXAMPLE 1 Preparation of(±)-(2-(2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide

[0058] 1,1′-Carbonyldiimidazole (4.5 g) was added to a solution of1-(2-thienyl)-1,2-ethanediol (1.0 g 6.9 mmol) in dichloromethane (15 mL)at 5°. The reaction mixture was allowed to come to room temperature withstirring over one hour. Ten ml of an aqueous solution of ammoniumhydroxide (28% NH3 in water) was added at 5°. The reaction mixture wasstirred for 1 hour at room temperature, extracted with ethyl acetate,washed with 0.5N aqueous hydrochloric acid, saturated sodium bicarbonateand brine. The extracts were dried over sodium sulfate, filtered,concentrated and purified by recrystallization from dichloromethane toyield the title compound as a white solid (1.2 g, yield 74%). M.p.158-159° (from dichloromethane). [α]_(D) ^(24′)=0′ (c=0.005, methanol).

EXAMPLE 2 Preparation of(+)-(2R)-(2-(2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide

[0059] The title compound was prepared in accordance with the procedureof Example 1, except that (+)-(1R)-1-(2-thienyl)-1,2-ethanediol (M.p.48˜50° from carbon tetrachloride) was used instead of(±)-1-(2-thienyl)-1,1-ethandiol. M.p. 183-184° (from dichloromethane).[α]_(D) ^(24′)=+63 (c=0.005, methanol).

EXAMPLE 3 Preparation of(−)-(2S)-(2-(2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide

[0060] The title compound was prepared in accordance with the procedureof Example 1, except that (−)-(1S)-1-(2-thienyl)-1,2-ethanediol (M.p.48˜50° from carbon tetrachloride) was used instead of(±)-1-(2-thienyl)-1,1-ethandiol. M.p. 184-185° (from dichloromethane).[α]_(D) ^(24′)=−56 (c=0.005, methanol).

EXAMPLE 4 Preparation of(±)-(2-(5-chloro-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide

[0061] The title compound was prepared in accordance with the procedureof Example 1, except that (±)-1-(5-chloro-2-thienyl)-1,2-ethanediol(M.p. 50˜51° from carbon tetrachloride) was used instead of(±)-1-(2-thienyl)-1,1-ethandiol. M.p. 154-156° (from dichloromethane).[α]_(D) ^(24′)=0′ (c=0.005, methanol).

EXAMPLE 5 Preparation of(+)-(2R)-(2-(5-chloro-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide

[0062] The title compound was prepared in accordance with the procedureof Example 1, except that (+)-(1R)-1-(5-chloro-2-thienyl)-1,2-ethanediol(M.p. 78˜80° from carbon tetrachloride) was used instead of(±)-1-(2-thienyl)-1,1-ethandiol. M.p. 185-186° (from dichloromethane).[α]_(D) ^(24′)=+55 (c=0.005, methanol).

EXAMPLE 6 Preparation of(−)(2S)-(2-(5-chloro-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide

[0063] The title compound was prepared in accordance with the procedureof Example 1, except that (−)-(1S)-1-(5-chloro-2-thienyl)-1,2-ethanediol(M.p. 77˜78° from carbon tetrachloride) was used instead of(±)-1-(2-thienyl)-1,1-ethandiol. M.p. 185-186° (from dichloromethane).[α]_(D) ^(24′)=−52 (c=0.005, methanol).

EXAMPLE 7 Preparation ofN-methyl-(2-(5-chloro-2-thienyl)-2-(N-methylcarbamoyloxyethyl)oxocarboxamide

[0064] The title compound was prepared in accordance with the procedureof Example 1, except that methylamine was used instead of ammoniumhydroxide. M.p. 104-106° (from hexane:ethyl acetate=5:1).

EXAMPLE 8 Preparation of(2-(5-phenyl-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide

[0065] The title compound was prepared in accordance with the procedureof Example 1, except that 1-(5-chloro-2-thienyl)-1,2-ethanediol (M.p.77˜78° from carbon tetrachloride) was used instead of(±)-1-(2-thienyl)-1,1-ethandiol. M.p. 202-203° (from methanol).

EXAMPLE 9 Preparation of(2-(3,4,5-trichloro-2-thienyl)-2-carbomoyloxyethyl)oxocarboxamide

[0066] The title compound was prepared in accordance with the procedureof Example 1 utilizing 1-(3,4,5-trichloro-2-thienyl)-1,2-ethanediol asthe starting material. M.p. 193-197° (from dichloromethane).

EXAMPLE 10 Preparation of(2-(5-methyl-2-thienyl)-2-carbomoyloxyethyl)oxocarboxamide

[0067] The title compound was prepared in accordance with the procedureof Example 1 utilizing 1-(5-methyl-2-thienyl)-1,2-ethanediol as thestarting material. M.p. 172-173° (from dichloromethane).

EXAMPLE 11 Preparation of(2-(2,5-dichloro-3-thienyl)-2-carbomoyloxyethyl)oxocarboxamide

[0068] The title compound was prepared in accordance with the procedureof Example 1 utilizing 1-(2,5-dichloro-3-thienyl)-1,2-ethanediol as thestarting material. M.p. 137-138° (from ether).

EXAMPLE 12 Preparation of(2-(3-trichloro-2-thienyl)-2-carbomoyloxyethyl)oxocarboxamide

[0069] The title compound was prepared in accordance with the procedureof Example 1 utilizing 1-(3-chloro-2-thienyl)-1,2-ethanediol as thestarting material. M.p. 153-155° (from dichloromethane).

EXAMPLE 13 Preparation of(2-(2-benzothienyl)-2-carbomoyloxyethyl)oxocarboxamide

[0070] The title compound was prepared in accordance with the procedureof Example 1 utilizing 1-(2-benzothienyl)-1,2-ethanediol as the startingmaterial. M.p. 195° (from dichloromethane).

EXAMPLE 14 Preparation of(2-(5-trifluoromethyl-2-thienyl)-2-carbomoyloxyethyl)oxocarboxamide

[0071] The title compound was prepared in accordance with the procedureof Example 1 utilizing 1-(5-trifluoromethyl-2-thienyl)-1,2-ethanediol asthe starting material. M.p. 159-160° (from dichloromethane).

EXAMPLE 15 Preparation of(2-(5-tert-butyl-2-thienyl)-2-carbomoyloxyethyl)oxocarboxamide

[0072] The title compound was prepared in accordance with the procedureof Example 1 utilizing 1-(5-tert-butyl -2-thienyl)-1,2-ethanediol as thestarting material. M.p. 132-155° (from carbon tetrachloride).

EXAMPLE 16 Preparation of(2-(5-cyano-2-thienyl)-2-carbomoyloxyethyl)oxocarboxamide

[0073] The title compound was prepared in accordance with the procedureof Example 1 utilizing 1-(5-cyano-2-thienyl)-1,2-ethanediol as thestarting material. M.p. 149-151° (from dichloromethane).

EXAMPLE 17 Preparation of(±)-(2-(5-bromo-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide

[0074] N-bromosuccinimide (1.79 g) was added in portions to a solutionof (±)-(2-(2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide (2.2 g 9.5mmol) in 40 ml of a 1:1 mixture of chloroform and acetic acid. Theresulting suspension was stirred for 24 hours. The reaction mixture wasthen diluted with an equal volume of water and the separated organiclayer was recovered, and sequentially washed with potassium hydroxidesolution and water. The extracts were dried over sodium sulfate,filtered, concentrated and purified by recrystallization fromdichloromethane to yield the title compound as a white solid (2.2 g).M.p. 160-161° (from dichloromethane).

EXAMPLE 18 Preparation of(+)-(2R)-(2-(5-bromo-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide

[0075] The title compound was prepared in accordance with the procedureof Example 17, utilizing(+)-(2R)-(2-(2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide as thestarting material. M.p. 181-182° (from dichloromethane). [α]_(D)^(24′)=+46′ (c=0.005, methanol).

EXAMPLE 19 Preparation of(−)-(2S)-(2-(5-bromo-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide

[0076] The title compound was prepared in accordance with the procedureof Example 17, except that the starting material was(−)-(2S)-(2-(2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide instead of(±)-(2-(2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide. M.p. 181-182°(from dichloromethane). [α]_(D) ^(24′)=−46′ (c=0.005, methanol).

EXAMPLE 20 Preparation of(2-(5-nitro-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide

[0077] In 4 ml of acetic anhydride there was suspended(2-(2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide (0.50 g) and theresulting mixture was cooled to 0°. A mixture of nitric acid (60% inwater 0.37 g) in 4 ml of acetic acid was added dropwise and the mixturewas stirred at room temperature for 1.5 hours, poured into 100 ml of icewater, extracted with ethyl acetate and washed with saturated brine. Theextracts were dried over sodium sulfate, filtered, concentrated andpurified by recrystallization from ether to yield the title compound asa yellow solid (0.07 g, yield 12%). M.p. 145-1847 (from ether).

EXAMPLE 21 Preparation of (2-(2-thienyl)-2-hydroxyethyl)oxocarboxamide

[0078] 1,1′-Carbonyldiimidazole (1.13 g) was added to a solution of1-(2-thienyl)-1,2-ethanediol (1.0 g) in 20 ml of dichloromethane at 5°.The reaction mixture was allowed to warm to room temperature, stirredfor one hour and then concentrated in vacuo to yield1-(2-thienyl)-1,2-ethanediol carbonate (1.07 g, 90.7% yield) as acolorless oil after chromatographic purification. The product wasdissolved in 20 ml of tetrahydrofuran and 2 g of ammonium hydroxide(equivalent to 28% ammonia in water) was added thereto at 0°. Thereaction mixture was slowly warmed to room temperature and was stirredthereafter for a further hour and then concentrated in vacuo to yield(2-(2-thienyl)-2-hydroxyethyl)oxocarboxamide (0.30 g, yield 25%) as awhite solid after chromatographic purification. M.p. 71-73° (fromdichloromethane).

EXAMPLE 22 Preparation of(2-(5-chloro-2-thienyl)-2-hydroxyethyl)oxocarboxamide

[0079] The title compound was prepared in accordance with the procedureof Example 21, utilizing 1-(5-chloro-2-thienyl)-1,2-ethanediol as thestarting material. M.p. 68-72° (from benzene).

EXAMPLE 23 Preparation of(2-(5-chloro-2-thienyl)-2-carbamoyloxy)ethan-1-ol

[0080] Imidazole (0.45 g) was added to a solution of1(5-chloro-2-thienyl)-1,2-ethanediol (1.0 g, 5.6 mmol) andtert-butyldimethylsilyl chloride (0.80 g) in N,N-dimethylformamide (5ml) at 5°. The reaction mixture was allowed to come to room temperatureand stirred 1 hour, extracted with ethyl acetate, washed with 0.5Naqueous hydrochloric acid, saturated sodium bicarbonate and brine. Theextracts were dried over sodium sulfate, filtered, concentrated invacuo. 1-tert-butyldimethylsilyloxy-2-(5-chloro-2-thienyl)ethan-1-ol(1.14 g) was obtained as a colorless oil after a chromatographicpurification. 1,1′-Carbonyldiimidazole (0.95 g) was added to a solutionof the foregoing alcohol (1.14 g 3.9 mmol) in dichloromethane (20 mL) at5°. The reaction mixture was allowed to come to room temperature andstirred 1 hour. Ammonium hydroxide (equivalent to 28% ammonia in water,10 ml) was added at 5°. The reaction mixture was stirred for 1 hour atroom temperature, extracted with ethyl acetate, washed with 0.5N aqueoushydrochloric acid, saturated sodium bicarbonate and brine. The extractswere dried over sodium sulfate, filtered, concentrated in vacuo.1-tert-butyldimethylsilyloxy-2-(5-chloro-2-thienyl)-2-carbamoyloxyethane(0.47 g) was obtained as a colorless oil after a chromatographicpurification.

[0081] Tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran 2ml) was added to a solution of the carboxamide formed above (0.47 g 1.6mmol) in tetrahydrofuran (10 mL) at 5°. The reaction mixture was stirred1 hour, extracted with ethyl acetate, washed with 0.5N aqueoushydrochloric acid, saturated sodium bicarbonate and brine. The extractswere dried over sodium sulfate, filtered, concentrated in vacuo.(2-(5-chloro-2-thienyl)-2-carbamoyloxy)ethan-1-ol (0.14 g) was obtainedas a white solid after a chromatographic purification. M.p. 117-120′C(from dichloromethane).

EXAMPLE 24 Preparation of(2-(2-pyridyl)-2-carbamoyloxyethyl)oxocarboxamide

[0082] The title compound was prepared in accordance with the procedureof Example 1 utilizing 1-(2-pyridyl)-1,2-ethanediol as the startingmaterial in place of 1-(2-thienyl)-1,2-ethanediol. M.p. 173-174′C (fromdichloromethane).

EXAMPLE 25 Preparation of (2-(2-pyridyl)-2-hydroxyethyl)oxocarboxamide

[0083] The title compound was prepared in accordance with the procedureof Example 21 utilizing 1-(2-pyridyl)-1,2-ethanediol as the startingmaterial. M.p. 116-120° (from dichloromethane).

EXAMPLE 26 Preparation of (2-(2-pyridyl)-2-carbamoyloxy)ethan-1-ol

[0084] The title compound was prepared in accordance with the procedureof Example 23 utilizing 1-(2-pyridyl)-1,2-ethanediol as the startingmaterial. M.p. 123-124° (from dichloromethane).

EXAMPLE 27 Preparation ofN-methyl-(2-(2-pyridyl)-2-(N-methylcarbamoyloxyethyl)oxocarboxamide

[0085] The title compound was prepared in accordance with the procedureof Example 1 utilizing methylamine in place of ammonium hydroxide. M.p.114-115° (from chloroform/ether).

EXAMPLE 28 Preparation of(2-(2-furanyl)-2-carbamoyloxyethyl)oxocarboxamide

[0086] The title compound was prepared in accordance with the procedureof Example 1 utilizing 1-(2-furanyl)-1,2-ethanediol as the startingmaterial. M.p. 155-560° (from dichloromethane).

EXAMPLE 29 Preparation of(2-(4-methyl-5-thiazolyl)-2-carbamoyloxyethyl)oxocarboxamide.

[0087] The title compound was prepared in accordance with the procedureof Example 1 utilizing 1-(4-Methyl-5-thiazolyl)-1,2-ethanediol as thestarting material. M.p. 166-168′C (from dichloromethane).

EXAMPLE 30 Preparation of(2-(2-indolyl)-2-carbamoyloxyethyl)oxocarboxamide

[0088] The title compound was prepared in accordance with the procedureof Example 1 utilizing 1-(2-Indolyl)-1,2-ethanediol as the startingmaterial. M.p. 145-146° (from diethyl ether).

EXAMPLE 31 Preparation of(2-(5-trimethylsilyl-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide

[0089] The title compound was prepared in accordance with the procedureof Example 1 utilizing 1-(5-trimethylsilyl-2-thienyl)-1,2-ethanediol asthe starting material. M.p. 138-140′C (from dichloromethane).

What is claimed is;
 1. A compound represented by the formula:

wherein A is a heterocyclic moiety optionally substituted by one or moresubstituents selected from the group consisting of alkyl, aryl, halogen,trihalomethyl, trihalomethoxy, trialkylsilyl, S(O)R, SO₂R, SO₂NRR′,SO₃R, SR, NO₂, NRR′, OR, CN, C(O)R, OC(O)R, NHC(O)R, CO₂R and CONRR′,wherein R and R′ are independently hydrogen, alkyl or aryl; B₁ and B₂are independently hydroxy or OCONR₁R₂, provided that B₁ and B₂ are notsimultaneously hydroxy,: and R₁ and R₂ are independently selected fromthe group consisting of hydrogen, hydroxy, alkyl, alkoxy, alkylaryl,arylalkyl, aryl and aryloxy, and their enantiomers, enantiomericmixtures thereof, and pharmaceutically acceptable salts thereof.
 2. Acompound in accordance with claim 1, wherein said compound is a pureenantiomer or an enantiomeric mixture wherein one enantiomerpredominates.
 3. A compound in accordance with claim 1, wherein B₁ andB₂ are OCONH₂.
 4. A compound in accordance with claim 1, wherein onlyone of B₁ and B₂ is OCONH₂.
 5. A compound in accordance with claim 1,wherein A is selected from the group consisting of

wherein each of R₃, R₄ and R₅ is independently selected from the groupconsisting of hydrogen, alkyl and aryl, and X is selected from sulfur,oxygen and nitrogen.
 6. A compound in accordance with claim 5, wherein Ais

wherein each of R₃, R₄ and R₅ is independently selected from the groupconsisting of hydrogen, alkyl and aryl, and X is selected from sulfur,oxygen and nitrogen.
 7. A compound in accordance with claim 6, wherein Ais

wherein each of R₃, R₄ and R₅ is independently selected from the groupconsisting of hydrogen, alkyl and aryl.
 8. A compound in accordance withclaim 1, wherein said compound is(±)-(2-(5-chloro-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide.
 9. Acompound in accordance with claim 1, wherein said compound is(+)-(2R)-(2-(5-chloro-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide; 10.A compound in accordance with claim 1, wherein said compound is(−)-(2S)-(2-(5-chloro-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide; 11.A compound in accordance with claim 1, wherein said compound is(2-(5-trifluoromethyl-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide. 12.A compound in accordance with claim 1, wherein said compound is(2-(5-bromo-2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide.
 13. Apharmaceutical composition comprising an effective amount of a compoundof in accordance with claim 1 for treating disorders of the centralnervous system.
 14. A pharmaceutical composition in accordance withclaim 13, wherein the central nervous systems disorder being treated isselected from the group consisting of convulsions, epilepsy, stroke,neurogenic pain and muscle spasm.
 15. A pharmaceutical composition inaccordance with claim 13, wherein said compound is a pure enantiomer oran enantiomeric mixture wherein one enantiomer predominates.
 16. Amethod for the treatment of a central nervous system disorder whichcomprises administering to a host requiring such treatment an effectiveamount of a compound in accordance with claim
 1. 17. A method inaccordance with claim 16, wherein said compound is a pure enantiomer oran enantiomeric mixture wherein one enantiomer predominates.